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Notch signaling pathway in cancer:from mechanistic insights to targeted therapies

Signal Transduction and Targeted Therapy 2024年第6期9卷 2527-2563页

作者： Qingmiao Shi Chen Xue Yifan Zeng Xin Yuan Qingfei Chu Shuwen Jiang Jinzhi Wang Yaqi Zhang Danhua Zhu Lanjuan Li State Key Laboratory for Diagnosis and treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Notch signaling,renowned for its role in regulating cell fate,organ development,and tissue homeostasis across metazoans,is highly conserved throughout *** Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences,typically necessitating receptor-ligand interaction to initiate classical Notch signaling *** evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer *** of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies,closely linked to cancer proliferation,invasion,and ***,the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells,thereby enhancing cancer *** regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive ***,the Notch signaling pathway is implicated in conferring chemoresistance to tumor ***,a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch *** review focuses on the research progress of the Notch signaling pathway in cancers,providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of ***,the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy,aiming to offer new insights into therapeutic strategies for human malignancies.

关键词： Notch invasion involvement

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Study on the anti-inflammatory mechanism of moxibustion in rheumatoid arthritis in rats based on phospholipaseA2 signaling inhibition by Annexin 1

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Journal of Traditional Chinese Medicine 2024年第4期44卷 753-761页

作者： GUO Yanding LUO Kun ZHANG Linlin LU Wenting SHANG Yanan ZHONG Yumei HU Danhui YANG Xin ZHOU Haiyan Department of Acupuncture-Moxibustion and Tuina the Third Affiliated HospitalChengdu University of Traditional Chinese Medicine external treatment center First People's Hospital of Chengdu Department of Chengdu Integrated Traditional Chinese Medicine and Western Medicine Hospital Department of Health Rehabilitation School Chengdu University of Traditional Chinese Medicine

OBJECTIVE: To determine whether moxibustion had an anti-inflammatory effect on rheumatoid arthritis(RA) by regulating Annexin 1 expression and interfering with the phospholipaseA2 signaling pathway. METHODS: Thirty male Sprague-Dawley rats were randomly categorized into five groups(six rats per group): blank control(CON) group, RA model(RA) group, moxibustion(MOX) group, Annexin 1 lentiviral intervention(RNAi-Anxa1) group, and Annexin 1 lentiviral intervention + moxibustion(RNAi-Anxa1 + MOX) group. The rats in the RNAi-Anxa1 and the RNAi-Anxa1 + MOX groups were injected with the lentiviral vector-mediated RNAi-Anxa1 into the rat foot pad. An experimental RA rat model was established by injecting Freund's complete adjuvant(FCA) into the RA, MOX, RNAi-Anxa1, and RNAi-Anxa1 + MOX groups. Rats in the MOX and RNAiAnxa1 + MOX groups received moxibustion treatment. After modeling, using moxibustion “Shenshu(BL23)” and “Zusanli(ST36)”, each point is 5 times, bilateral alternating, once a day, 6 times for a course of treatment, between the courses of rest for a one day. A total of three treatment courses were conducted. Both bilateral pad thicknesses were measured using Vernier calipers on experimental days 1, 7, 14, 21, and 28. The expression of cPLA2α signaling in the synovium of diseased joints was observed using Western blot. The pathology of the rat ankle synovium was observed using hematoxylineosin(HE) staining. Interleukin(IL)-1β, IL-10, prostaglandin E2(PGE2), and leukotriene B4(LTB4) were detected using enzyme-linked immunosorbent assay. RESULTS: Moxibustion increased the levels of Annexin 1 and decreased the inflammatory response in rats with RA. After increasing the expression of Annexin 1, the phosphorylated expression of cPLA2α was inhibited, the serum levels of IL-1β, PGE2, and LTB4 decreased, and the level of IL-10 increased. In moxibustion treated RA rats after the Annexin 1 lentiviral intervention, the serum levels of IL-1β, PGE2, LTB4, and IL-10 were almost

关键词： annexins arthritis, rheumatoid group IV phospholipases A2 moxibustion signal transduction

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Enrichment of anammox biomass during mainstream wastewater treatment driven by achievement of partial denitrification through the addition of bio-carriers

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Journal of Environmental Sciences 2024年第3期137卷 181-194页

作者： Yuqing Ma Bo Wang Xiaodi Li Shuo Wang Wen Wang Yongzhen Peng National Engineering Laboratory for Advanced Municipal Wastewater treatment and Reuse Technology Engineering Research Center of BeijingBeijing University of TechnologyBeijing 100124China

Anammox is widely considered as the most cost-effective and sustainable process for nitrogen ***,how to achieve the enrichment of anammox biomass remains a challenge for its large-scale application,especially in mainstream wastewater *** this study,the feasibility of enrichment of anammox biomass was explored through the realization of partial denitrification and the addition of *** using ordinary activated sludge,a sequencing batch reactor(SBR)followed by an up-fow anaerobic sludge bed(UASB)was operated at 25±2℃ for 214 *** long-term operation was divided into five phases,in which SBR and UASB were started-up in Phases I and II,*** eliminating oxygen and adjusting the infow ratios in Phases III-V,advanced nitrogen removal was achieved with the effuent total nitrogen being 4.7 mg/L and the nitrogen removal efficiency being 90.5%in Phase *** in-situ and ex-situ activity tests demonstrated the occurrence of partial denitrification and ***,16S rRNA high-throughput sequencing analysis revealed that Candidatus Brocadia was enriched from below the detection limit to in biofilms(0.4%in SBR,2.2%in UASB)and the foc sludge(0.2%in SBR,1.3%in UASB),while Thauera was mainly detected in the foc sludge(8.1%in SBR,8.8%in UASB),which might play a key role in partial ***,this study provides a novel strategy to enrich anammox biomass driven by rapid achievement of partial denitrification through the addition of bio-carriers,which will improve large-scale application of anammox processes in mainstream wastewater treatment.

关键词： Enrichment Anammox biomass Bio-carriers Partial denitrification Mainstream wastewater

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Hemoperfusion and continuous veno-venous hemodiafiltration for eliminating chlorfenapyr in poisoning patients

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World Journal of Emergency Medicine 2024年第3期15卷 235-237页

作者： Yanqing Liu Xiaoxia Lu Haochun Wang Ming Niu Renzheng Zhang Zhongying Liu Limei Han Xiaobo Peng Xigang Zhang Poisoning treatment Department Senior Department of Hematologythe Fifth Medical Center of PLA General HospitalBeijing 100039China

Chlorfenapyr is a liposoluble insecticide belonging to the pyrrole *** is activated when the N-ethoxymethyl side chain breaks,forming a toxic metabolite,which uncouples oxidative phosphorylation in the mitochondria,inhibits the production of adenosine triphosphate (ATP),and leads to the death of cells and targe organisms.[1] Symptoms of chlorfenapyr poisoning in patients are mild and atypical in the early stage,especially in patients receiving low dose exposure;however,such cases are rare and may be ignored by physicians,often leading to delayed treatment.[2,3].

关键词： patients perfusion eliminating

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Astragaloside IV Alleviates Acute Liver Failure Induced by D-GalN/LPS by Upregulating Autophagy and Reducing Inflammation

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Infectious Microbes & Diseases 2024年第1期6卷 20-28页

作者： Meng Hong Wenwen Lian Ying Yang Zhi Chen State Key Laboratory for Diagnosis and treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina

Acute liver failure(ALF)is a life-threatening condition that manifests in an extremely serious manner and progresses *** following study investigated the protective effect of astragaloside IV(AS-IV),a traditional Chinese drug,on ALF,and its underlying mechanisms,focusing on autophagy and inflammation *** were randomly divided into a saline group,a D-galactosamine and lipopolysac-charide(D-GalN/LPS)group and an AS-IV *** analysis,immunohistochemistry,cytometric bead array,high-throughput quantitative PCR,flow cytometry and Western analysis were used to assess inflammation and liver damage 5 hours after D-GalN/LPS *** IV treatment reduced mortality by alleviating D-GalN/LPS–induced hepatic damage and decreasing inflammation(decreasing Ly6c+monocyte levels,reducing inflammatory cytokines and increasing anti-inflammatory factors)as well as upregulating ***,PCR array was used to detect expression of autophagy-related genes,which demonstrated a Log2 fold change in gene expression between the AS-IV and D-GalN/LPS groups ranging from 1.19 to-3.53,with Tnfsf10 showing the largest alteration be-tween the two *** data suggest that AS-IV may alleviate ALF by upregulating autophagy and reducing inflammation,and it may therefore be an interesting drug for alleviating ALF.

关键词： astragaloside IV acute liver failure inflammation autophagy

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Human Placental Mesenchymal Stem Cells Relieve Primary Sclerosing Cholangitis via Upregulation of TGR5 in Mdr2-/-Mice and Human Intrahepatic Cholangiocyte Organoid Models

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Research 2024年第2期2023卷 355-372页

作者： Qigu Yao Wenyi Chen Yingduo Yu Feiqiong Gao Jiahang Zhou Jian Wu Qiaoling Pan Jinfeng Yang Lingling Zhou Jiong Yu Hongcui Cao Lanjuan Li State Key Laboratory for the Diagnosis and treatment of Infectious Diseases Cllaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affliated HospitalZhejang University School of Medicine79 Qingchun Rd.Hangzhou 310003China National Clinical Research center for Infectious Diseases HangzhouChina Key Laboratory of Diagnosis and treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province 79 Qingchun Rd.Hangzhou 310003China Jjinan Microecological Biomedicine Shandong Laboratory Jinan 250117China

Primary sclerosing cholangitis(PSC)is a biliary disease accompanied by chronic inflammation of the liver and biliary *** stem cells(MSCs)are used to treat liver diseases because of their immune regulation and regeneration-promoting *** study was performed to explore the therapeutic potential of human placental MSCs(hP-MSCs)in PSC through the Takeda G protein-coupled receptor 5(TGR5)receptor *** tissues were collected from patients with PSC and healthy donors(n=4)for RNA sequencing and intrahepatic cholangiocyte organoid ***-MSCs were injected via the tail vein into Mdr2^(-/-),bile duct ligation(BDL),and 3,5-diethoxycarbonyl-1,4-dihydrocollidine(DDC)mouse models or co-cultured with organoids to confirm their therapeutic effect on biliary *** in bile acid metabolic profile were analyzed by liquid chromatography/tandem mass spectrometry(LC-MS/MS).Compared with healthy controls,liver tissues and intrahepatic cholangiocyte organoids from PSC patients were characterized by inflammation and cholestasis,and marked downregulation of bile acid receptor TGR5 ***-MSC treatment apparently reduced the inflammation,cholestasis,and fibrosis in Mdr2^(-/-),BDL,and DDC model *** activating the phosphatidylinositol 3 kinase/extracellular signal-regulated protein kinase pathway,hP-MSC treatment promoted the proliferation of cholangiocytes,and affected the transcription of downstream nuclear factorκB through regulation of the binding of TGR5 and Pellino3,thereby affecting the cholangiocyte inflammatory phenotype.

关键词： inflammation TGR5 Human

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Development of a new Cox model for predicting long-term survival in hepatitis cirrhosis patients underwent transjugular intrahepatic portosystemic shunts

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World Journal of Gastrointestinal Surgery 2024年第2期16卷 491-502页

作者： Yi-Fan Lv Bing Zhu Ming-Ming Meng Yi-Fan Wu Cheng-Bin Dong Yu Zhang Bo-Wen Liu Shao-Li You Sa Lv Yong-Ping Yang Fu-Quan Liu Liver Disease Minimally Invasive Diagnosis and treatment center Beijing Shijitan HospitalCapital Medical UniversityBeijing 100038China Liver Vascular Disease Diagnosis and treatment center The Fifth Medical Center of Chinese People's Liberation Army General HospitalBeijing 100039China

BACKGROUND Transjugular intrahepatic portosystemic shunt(TIPS)placement is a procedure that can effectively treat complications of portal hypertension,such as variceal bleeding and refractory ***,there have been no specific studies on predicting long-term survival after TIPS *** To establish a model to predict long-term survival in patients with hepatitis cirrhosis after *** A retrospective analysis was conducted on a cohort of 224 patients who un-derwent TIPS *** univariate and multivariate Cox regression analyses,various factors were examined for their ability to predict survival at 6 years after ***,a composite score was formulated,encompassing the indication,shunt reasonability,portal venous pressure gradient(PPG)after TIPS,percentage decrease in portal venous pressure(PVP),indocyanine green retention rate at 15 min(ICGR15)and total bilirubin(Tbil)***,the performance of the newly developed Cox(NDC)model was evaluated in an in-ternal validation cohort and compared with that of a series of existing *** The indication(variceal bleeding or ascites),shunt reasonability(reasonable or unreasonable),ICGR15,post-operative PPG,percentage of PVP decrease and Tbil were found to be independent factors affecting long-term survival after TIPS *** NDC model incorporated these parameters and successfully identified patients at high risk,exhibiting a notably elevated mortality rate following the TIPS procedure,as observed in both the training and validation ***,in terms of predicting the long-term survival rate,the performance of the NDC model was significantly better than that of the other four models[Child-Pugh,model for end-stage liver disease(MELD),MELD-sodium and the Freiburg index of post-TIPS survival].CONCLUSION The NDC model can accurately predict long-term survival after the TIPS procedure in patients with hepatitis cirrhosis,help identify high-risk patients

关键词： Transjugular intrahepatic portosystemic shunt Long-term survival Predictive model

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Moxibustion of Zusanli(ST36)and Shenshu(BL23)alleviates the inflammation of rheumatoid arthritis in rats through regulating macrophage migration inhibitory factor/glucocorticoids signaling

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Journal of Traditional Chinese Medicine 2024年第2期44卷 353-361页

作者： ZHANG Linlin ZHONG Yumei LU Wenting SHANG Yanan GUO Yanding LUO Xiaochao CHEN Yang LUO Kun HU Danhui YU Huiling ZHOU Haiyan Acupuncture and Moxibustion College Chengdu University of Traditional Chinese MedicineChengdu 610075China Department of Painology First People's Hospital of ChengduChengdu 610095China Chinese Evidence-Based Medicine Centre West China HospitalSichuan UniversityChengdu 610044China Traditional Chinese Medicine College Chongqing Medical UniversityChongqing 400016China external treatment center First People's Hospital of ChengduChengdu 610095China

OBJECTIVE:To test the hypothesis that moxibustion may inhibit rheumatoid arthritis(RA)synovial inflammation by regulating the expression of macrophage migration inhibitory factor(MIF)/glucocorticoids(GCs).METHODS:Fifty male Sprague-Dawley rats were randomly divided into five groups(n=10 each):blank Control(CON)group,RA Model(RA)group,Moxibustion(MOX)group,MIF inhibitor(S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester(ISO-1)group,and Moxibustion+MIF inhibitor ISO-1(MOX+ISO-1)*** in the ISO-1 group and ISO-1+MOX group were intraperitoneally injected with the inhibitor *** rats in the RA group,ISO-1 group,MOX group,and ISO-1+MOX group were injected with Freund's complete adjuvant(FCA)in the right hind footpad to establish an experimental RA rat *** the MOX group and MOX+ISO-1 group,rats were treated with *** thickness of the footpads of the rats in each group was measured at three-time points before,after modeling and after moxibustion *** contents of serum MIF,corticosterone(CORT),tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β)were detected by enzyme-linked immunosorbent assay;and the contents of synovial MIF were detected by Western ***-eosin(HE)staining method was used to observe the pathological changes of synovial tissue under a section light microscope,and pathological scoring was performed according to the grading standard of the degree of synovial tissue ***:Moxibustion was found to reduce the level of MIF and alleviate inflammation in RA rats in this *** addition,after inhibiting the expression of MIF,the level of CORT increased,and the level of TNF-α *** RA rats with inhibited MIF by moxibustion,the level of CORT was almost unchanged,but the level of TNF-α further *** correlation analysis data suggested that MIF was positively related to the expression of TNF-α and negatively correlated with the expression of ***:Reducing MIF to

关键词： rheumatoid arthritis macrophage migration inhibitory factor moxibustion corticosterone glucocorticoids

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MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

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Asian Journal of Pharmaceutical Sciences 2024年第1期19卷 119-134页

作者： Wenyi Chen Feiyan Lin Xudong Feng Qigu Yao Yingduo Yu Feiqiong Gao Jiahang Zhou Qiaoling Pan Jian Wu Jinfeng Yang Jiong Yu Hongcui Cao Lanjuan Li State Key Laboratory for the Diagnosis and treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesNational Medical Center for Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Jinan Microecological Biomedicine Shandong Laboratory Jinan 250117China Key Laboratory of Diagnosis and treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province Hangzhou 310003China

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage *** placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver ***,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC *** results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in ***,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular ***,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.

关键词： Mesenchymal stem cell Exosomes Primary sclerosing cholangitis Fibrosis Organoids Th17

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Mitochondrial dysfunction: A promising therapeutic target for liver diseases

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Genes & Diseases 2024年第3期11卷 324-337页

作者： Ping Chen Lichao Yao Mengqin Yuan Zheng Wang Qiuling Zhang Yingan Jiang Lanjuan Li Department of Infectious Diseases Renmin Hospital of Wuhan UniversityWuhanHubei 430060China State Key Laboratory for Diagnosis and treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang 310003China

The liver is an important metabolic and detoxification organ and hence demands a large amount of energy,which is mainly produced by the *** tissues of pa-tients with alcohol-related or non-alcohol-related liver diseases contain ultrastructural mito-chondrial lesions,mitochondrial DNA damage,disturbed mitochondrial dynamics,and compromised ATP *** of mitochondrial reactive oxygen species in-duces oxidative damage to mitochondrial proteins and mitochondrial DNA,decreases mito-chondrial membrane potential,triggers hepatocyte inflammation,and promotes programmed cell death,all of which impair liver *** DNA may be a poten-tial novel non-invasive biomarker of the risk of progression to liver cirrhosis and hepatocellular carcinoma in patients infected with the hepatitis B *** herein present a review of the mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases,such as hepatocellular carcinoma,viral hepatitis,drug-induced liver injury,alcoholic liver disease,and non-alcoholic fatty liver *** review also discusses mito-chondrion-centric therapies for treating liver diseases.

关键词： Chronic diseases Liverdamage Mesenchymalstem cell Mitochondrial dysfunction Oxidativestress

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